Respiratory diseases, such as allergic rhinitis, asthma, and chronic obstructive pulmonary disorders (COPD) are often debilitating conditions with high prevalence, affecting more than 155 million people in the developed world. Asthma is one of the common chronic diseases and is rapidly increasing by 20% to 50% per decade, particularly in children. Currently, there are 53 million patients in the major pharmaceutical markets. Constriction of the airways is the hallmark of chronic conditions such as asthma and COPD, and inflammation is common to all respiratory diseases affecting either the upper or lower airways. Bronchodilators, which may possess limited anti-inflammatory activity, are considered the first line of therapy for asthma. Steroids are considered the gold standard as anti-inflammatory therapy, but they possess other significant adverse effects. Effective therapeutics other than steroids are under intense investigation.
A group of four peptide hormones, originating from the 126-amino acid atrial natriuretic factor (ANF) prohormone, have been known for their vasodilator activity. These four peptide hormones, consisting of amino acids 1-30, 31-67, 79-98, and 99-126 of this prehormone, have been named long acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide (ANP), respectively for their most prominent effects (Angus R. M. et al., Clin Exp Allergy 1994, 24:784-788). The ANP sequence, particularly the C-terminal portion, is highly conserved among species (Seidman et al., Science, 1984, 226:1206-1209). It has been proposed to be useful for treatment of various cardiovascular, respiratory, cancerous and renal diseases (Vesely, D. L. Cardiovascular, 2001, 51:647-658).
The C-terminal peptide of proANF (also known by the synonym proANP), ANP is a 28-amino acid hormone secreted by the cardiac atria and lung tissue Needleham, P. et al., N Engl J Med, 1986, 314:828-834). ANP has vasodilator, natriuretic and diuretic properties (Needleham, P. et al., N Engl J Med, 1986, 314:828-834). ANP infused at high concentrations reduces airway resistance in normal subjects (Hulks G. et al., Clin Sci 1990;79:51-55) and produces a significant bronchodilator response in patients with asthma. Inhaled ANP attenuates histamine- and methacholine (MCh)-induced bronchoconstriction (Hulks, G. et al., Br. Med J, 1992, 304:1156; Angus, R. M. et al., Clin Exp Allergy, 1994, 24:784-788); however, the amount of ANP required for efficacy and their short half-life limits their use for long-term modulation of airway hyper-responsiveness (Hamet, P. et al., Nephrologie, 1987, 8:7-12; Matsuse, H., et al., J Immunol, 2000, 164:6583-6582).
The present inventor has demonstrated prolonged amelioration of symptoms associated with respiratory allergy and asthma by delivery of pDNA-encoding various natriuretic hormone peptides (NHPs), or by delivery of the peptides themselves, which exhibit bronchodilatory and/or anti-inflammatory activity.